BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma

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Number of Participants With DLT- Phase I [ Time Frame: From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days ]

Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part

Progression-free Survival (PFS-6) at Six Months - Phase II [ Time Frame: At six months after randomization ]

PFS-6 is defined as probability of patients surviving to six months after randomization without progression. Disease progression was evaluated by an independent review committee and by the investigators, independently. The evaluation by the independent review committee was used for the primary outcome measure. The measurement "Number" the estimated PFS-6 value from the Kaplan-Meier curve of PFS.

Secondary Outcome Measures
:

Objective Tumor Response in Phase I [ Time Frame: From treatment start until the date of first documented progression or data cutoff at May 12, 2011, whichever came first, with a mean treatment duration of 69.7 days. ]

Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.

Objective Tumor Response in Phase II [ Time Frame: From randomization to until the date of first documented progression or data cutoff on July 15, 2016, whichever came first, with a mean treatment duration of 110.0 days ]

Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. Only data collected until cut-off date July 15, 2016 were considered.

Progression-free Survival (PFS)- Phase II Part [ Time Frame: from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months. ]

Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.

Trough plasma concentration of afatinib after multiple administration of 40 mg afatinib administered as monotherapy or in combination with 75 mg/m² temozolomide

Number of Participants With EGFRvIII Assessed by IHC Test. [ Time Frame: Baseline (during screening) ]

Number of participants with the epidermal growth factor receptor variant III (EGFRvIII) assessed by IHC test for the evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFRvIII by immunohistochemistry (IHC) test.

Number of participants with MGMT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry (IHC) test.

Number of participants with EGFR marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (IHC) test

Number of participants with PTEN marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Phosphatase and Tensin Homologue - a tumor suppressor gene/protein (PTEN) by immunohistochemistry (IHC) test.

Number of participants with PAKT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Serinethreonine kinase (PAKT) by immunohistochemistry (IHC) test.

Number of Participants With EGFR Assessed by FISH [ Time Frame: Baseline (during screening) ]

Number of participants with EGFR assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFR by fluorescent in situ hybridization (FISH).

Number of Participants With PTEN Assessed by FISH [ Time Frame: Baseline (during screening) ]

Number of participants with PTEN assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for PTEN by fluorescent in situ hybridization (FISH).

Number of Participants With Chromosomes (CEP7) Assessed by FISH [ Time Frame: Baseline (during screening) ]

Number of participants with Chromosomes (CEP7) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP7) by fluorescent in situ hybridization (FISH).

Number of Participants With Chromosomes (CEP10) Assessed by FISH [ Time Frame: Baseline (during screening) ]

Number of participants with Chromosomes (CEP10) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP10) by fluorescent in situ hybridization (FISH).

Number of Participants With Investigator Defined Drug−Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

Safety was assessed based on number of participants with investigator defined drug−related AEs, AEs leading to discontinuation of trial drug, All Serious Adverse events (AE) and other significant AEs (according to International Conference on Harmonisation (ICH) E3).

Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological

Number of Participants With Adverse Events, Graded According CTCAE - Phase I [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

Safety of Afatinib assesed based on Number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

Causes of Death - Phase I [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

Cause of the death reported during on treatment was due to disease progression.

Number of Participants With Investigator Defined Drug−Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

Safety was assessed based on number of participants with investigator defined drug−related AEs, AE leading to dose reduction, Adverse events (AEs) leading to discontinuation of trial drug and All Serious Adverse events (SAE).

Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological.

Number of Participants With Adverse Events, Graded According CTCAE - Phase II [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

Safety of Afatinib assessed based on the number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

Causes of Death - Phase II [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

Causes of death during on treatment.

Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion criteria:

Phase I Part:

Histologically-confirmed WHO Grade III or IV malignant glioma that is recurrent after prior chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade III or IV malignant glioma.

Age at least 18 years at entry

KPS at least 60%

Patients must have recovered from previous surgery and chemotherapy.

Written informed consent that is consistent with local law and ICH-GCP guidelines.

Phase II Part:

Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade IV malignant glioma and if prior treatment included temozolomide chemotherapy and radiotherapy.

Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1).

Age at least 18 years at entry

KPS at least 70%

Patients must have recovered from previous surgery and chemotherapy.

Written informed consent that is consistent with local law and ICH-GCP guidelines.

Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of study treatment.

Exclusion criteria:

Phase I and Phase II Parts:

Less than 12 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.

Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.

Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).

Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.

Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea.

Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.

Patient is <3 years free of another primary malignancy except: if the other primary malignancy is either not currently clinically significant or does not require active intervention (such as a basal cell skin cancer or a cervical carcinoma in situ). Existence of any other malignant disease is not allowed.